Direct receptor actions of MDMA

[BilZ0r]

I've long been of the view that MDMA has no significant direct receptor action in human use. A paper last week shook that opinion in the first read. They compare the effect of MDMA in normal animals, to those who have had their serotonin nearly completely depleted, hence, the serotonin releasing actions of MDMA wont exsist in animals with no serotonin. So only direct receptor serotonergic effects will be left.

Psychopharmacology (Berl). 2005 Jun 28;:1-8

Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse.

Fantegrossi WE, Kiessel CL, De La Garza R 2nd, Woods JH.

Division of Neuroscience, Yerkes National Primate Research Center, Emory University, 954 Gatewood Drive, Atlanta, GA, 30322, USA.

RATIONALE: Drug challenges in "intact" and p-chlorophenylalanine (p-CPA)-treated animals can be used to distinguish agents that act as direct serotonin (5-HT) agonists from agents that function as 5-HT releasers.

OBJECTIVES: The objective of the study was to investigate the effect of p-CPA treatment on the capacity of racemic 3,4-methylenedioxymethamphetamine (MDMA) and its stereoisomers to induce the head twitch response, hyperthermia, and locomotor stimulation in mice.

METHODS: Pretreatments with either 100 mg/kg p-CPA or equivolume saline were administered for three consecutive days. The following day, mice were either euthanized (to quantify 5-HT tone), tested with various doses of racemic MDMA or one of its enantiomers in the head twitch assay, or challenged with 32 mg/kg racemic MDMA or one of its enantiomers, while temperature and locomotor activity were monitored via radiotelemetry.

RESULTS: p-CPA reduced cortical 5-HT turnover by >70% without altering dopamine turnover. Racemic MDMA did not induce a significant head twitch response in intact or p-CPA-treated mice. S(+)-MDMA and R(-)-MDMA elicited similar head twitch curves in intact mice; p-CPA treatment attenuated this response when induced by S(+)-MDMA but not when elicited by R(-)-MDMA. Neither the hyperthermic nor locomotor-stimulant effects of racemic MDMA were altered by p-CPA treatment. The hyperthermic effects, but not the locomotor-stimulant effects, of S(+)-MDMA were attenuated in mice treated with p-CPA. R(-)-MDMA did not alter core temperature or induce significant locomotor stimulation in intact or p-CPA-treated mice.

CONCLUSIONS: The effects of S(+)-MDMA on core temperature and head twitch behavior are consistent with a mechanism involving 5-HT release, whereas the effects of R(-)-MDMA on head twitch behavior are consistent with a direct agonist mechanism of action. The actions of the racemate on core temperature and locomotor activity likely involve a combination of 5-HT release and direct agonism at 5-HT receptors.

The important thing to note their is the dose: 32mg/kg(IP). That is a fucker of a dose. Humans are taking more on the order of 1-2mg/kg, which reaches plasma concentrations of 1-2µM, and by my estimations, brain concentrations of about them same. Rats taking doses of 10mg/kg(IP) get a plasma concentration of ~6.2µM and a brain concentration of ~5µM... It also seems non-linear, as rats dosed with 15mg/kg get closer to 20µM in their brain. One could extrapolate to 32mg/kg and the rats have at least 40µM, if not 50-60µM.[1]

So this paper is looking at the effects MDMA has at 40-60µM, and then its not surprising at all that you get a significant direct receptor effect when MDMA has EC50s at 5-HT2A receptors in expressed systems of 5-10µM [2]. But of course, because in humans the brain concentration doesn't reach that high, (1-2µM), they wont be reaching a large effect on receptors, especially when they can get into transporters where they have a ~100nM affinity.

Though we can rule out OTHER receptors, for instance MDMA has a ~500nM affinity at the 5-HT2B receptor [3]

 

[xxuxx]

especially when they can get into transporters where they have a ~100nM affinity.

And at what concentrations do presynaptic pathways for MDMA metabolism have an overwhelming affinity?

(Did that q make sense?)

UM. Is direct action that which occurs at the synapse? Because I do know that the most accepted pathway for MDMA activity is that it makes the reuptake sites work in reverse. If MDMA is more likely to be metabolised before it reaches the synapse, because of the low concentration, then...etc.

I apologise. I'm really not at all up on the terminology.

 

[BilZ0r]

(Did that q make sense?)

Not to me.

A direct action is one directly at a classical receptor, i.e. the 5-HT2A receptor, as opposed to MDMA, releasing serotonin, which then acts at 5-HT2A... i.e. MDMA indirectly stimulates the 5-Ht2A receptor because it causes the release of serotonin.

 

[xxuxx]

^^^ Ooooh.

 

[C6H6]

Here is some more on this topic:

Psychopharmacology (Berl). 2005 Jul 6;:1-12 [Epub ahead of print]

Role of 5-HT(2A) and 5-HT(2C/B) receptors in the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on striatal single-unit activity and locomotion in freely moving rats.

Ball KT, Rebec GV.

Department of Psychology and Program in Neural Science, Indiana University, 1101 East 10th Street, Bloomington, IN, 47405, USA.

RATIONALE: Like amphetamine, a locomotor-activating dose of 3,4-methylenedioxymethamphetamine (MDMA) predominantly excites striatal single-unit activity in freely moving rats. Although both D(1)- and D(2)-like dopamine (DA) receptors play important roles in this effect, MDMA, unlike amphetamine, strongly increases both DA and serotonin (5-HT) transmission. OBJECTIVES: This study was conducted to investigate the 5-HT receptor mechanisms underlying the striatal effects of MDMA. METHODS: We recorded the activity of >200 single units in the striatum of awake, unrestrained rats in response to acute MDMA administration (5 mg/kg) combined with the selective blockade of either 5-HT(2A) or 5-HT(2C/B) receptors. RESULTS: Prior administration of SR-46349B (a 5-HT(2A) antagonist 0.5 mg/kg) blocked nearly all MDMA-induced striatal excitations, which paralleled its significant attenuation of MDMA-induced locomotor activation. Conversely, prior administration of SB-206553 (a 5-HT(2C/B) antagonist 2.0 mg/kg) had no effect on the amount of MDMA-induced locomotor activation or the distribution of single-unit responses to MDMA. However, a coefficient-of-variation analysis indicated significantly less variability in the magnitude of both MDMA-induced neuronal excitations and inhibitions in rats that were pretreated with SB-206553 compared to vehicle. Analysis of concurrent single-unit activity and behavior confirmed that MDMA-induced striatal activation was not merely due to behavioral feedback, indicating a primary action of MDMA. CONCLUSION: These results support and extend our previous findings by showing that 5-HT(2A) and 5-HT(2C/B) receptors differentially regulate the expression of MDMA-induced behavioral and striatal neuronal responses, either directly or through the modulation of DA transmission.

PMID: 16001122